The incidence of brain cancer in the U.S. is surprisingly high, and includes 15,000 new cases per year of the highly malignant primary brain cancer, glioblastoma multiforme (GBM), and about 150,000 cases per year of metastatic cancer to brain. The epidermal growth factor receptor (EGFR) plays an oncogenic role in over 100,000 cases of brain cancer per year, and is the number 1 target of new cancer therapeutics in development. Up to 50% of patients with brain cancer express mutant forms of the EGFR, which are generally resistant to drugs that block the wild type EGFR. Moreover, the success of anti-EGFR cancer therapeutics for the brain is limited by the presence of the blood-brain barrier (BBB), which is intact in the early phase of brain cancer, when treatment is still possible. None of the large molecule drugs (monoclonal antibodies, cancer vaccines, gene therapies) cross the BBB, and >98% of small molecule cancer therapeutics do not cross the BBB. Therefore, the development of BBB drug/gene targeting technologies is a crucial step in the war against cancer of the brain. The present work will exploit a new form of non-viral, non-invasive gene therapy of the brain for the treatment of EGFR-dependent GBM or metastatic cancer. The new gene delivery technology employs pegylated immunoliposomes (PILs) and is non-invasive, requiring only weekly intravenous injections. The PIL gene transfer technology will be combined with the power of antisense mechanisms to develop new gene therapies of brain cancer that are capable of >90% knockdown of either the wild type or mutant EGFR. Since RNA-based forms of antisense drugs are unstable in vivo, the present work will develop new plasmid based gene medicines that produce antisense RNA within the target cancer cell that specifically attack either the wild type or mutant EGFR mRNA. The EGFR antisense encoding gene medicine will be delivered to brain cancer with a genetically engineered recombinant protein that acts as a molecular Trojan horse (MTH). This MTH ferries the PIL carrying the gene medicine across the membrane barriers in the body that separate the blood from the nucleus of the brain cancer cell. The MTH triggers the sequential receptor-mediated transcytosis of the PIL across the BBB, and the receptor-mediated endocytosis of the PIL into the brain cancer cell.